BCL6 is a transcriptional repressor of the BTB-POZ (bric à brac, tramtrack, broad complex/pox virus zinc finger) family of proteins. It is required for normal development of germinal center (GC) B-cells and is also the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCLs), and constitutive expression of BCL6 in GC B-cells causes DLBCL in mice. DLBCLs are aggressive tumors that arise from germinal center (GC) B-cells and are the most common form of non-Hodgkin's lymphomas. BCL6 is required for survival of DLBCL cells and can limit their ability to respond to DNA damaging agents. It is also frequently expressed in follicular lymphomas (FLs), and may be required for survival of these tumors as well. DLBCL and FL collectively constitute ˜60-70% of B-cell lymphomas and the incidence of these tumors has been rising in recent decades. BLC6 binds to the SMRT co-repressor through a tight and unique interaction mediated by the N-terminal BTB/POZ domain of BCL6. Peptides that mimic the SMRT interface can displace SMRT from BCL6, de-repress BCL6 target genes and kill DLBCL cells. BCL6 has an N-terminal BTB domain that mediates transcriptional repression and a C-terminal C2H2 zinc finger that binds to a specific DNA consensus sequence. The two regions are linked by a second repression domain (RD2) that also has repressor activity. The BTB domain of BCL6 recruits the SMRT, N-CoR, and BCoR corepressors. The minimal binding domain of the SMRT, N-CoR, and BCoR corepressors maps to a conserved 17 amino acid sequence (BBD, BCL6 Binding Domain) that binds to a “lateral groove” motif on the BCL6 BTB domain dimer. This lateral groove/BBD interaction is required for the BCL6 domain to recruit the SMRT, N-CoR, and BCoR corepressors, and is essential for the repression activity of BCL6. The peptides contain a common aromatic residue that fits into a pocket within the lateral groove and they adopt a similar pseudo-structure upon binding. Also, the SMRT, N-CoR, and BCoR BBDs bind specifically to the BCL6-BTB but not to other BTB domains from any other protein member of the family.
Approximately 80% of patients with DLBCL responded to conventional chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), but less than 40% were likely to be cured. Randomized trials showed that the addition of rituximab (R) to conventional CHOP chemotherapy improves outcomes including overall survival, establishing R-CHOP as the standard of care. A recent analysis of outcomes on the US Intergroup Trial (E4494) comparing CHOP to R-CHOP and maintenance rituximab indicated that the benefit observed with the addition of rituximab was attributable to a powerful effect on the BCL6 negative cases only. Cases positive for BCL6 did not benefit from the addition of rituximab to CHOP chemotherapy. The mechanism by which the addition of rituximab to CHOP improves outcomes selectively in the BCL6 negative cases is unknown but could be related to antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, induction of apoptosis or an as yet uncharacterized effect unique to BCL6 negative DLBCL. These findings underscore the fact that the DLBCLs represent at least two biologically distinct diseases that will require different treatment approaches to improve upon current outcomes. To date, clinical trials for DLBCL have not distinguished between the different subgroups. Therapeutic strategies must be designed to specifically target BCL6 positive and negative DLBCL based upon their unique biological differences.